Central memory CD8⁺ T lymphocytes mediate lung allograft acceptance

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Abstract

Memory T lymphocytes are commonly viewed as a major barrier for long-term survival of organ allografts and are thought to accelerate rejection responses due to their rapid infiltration into allografts, low threshold for activation, and ability to produce inflammatory mediators. Because memory T cells are usually associated with rejection, preclinical protocols have been developed to target this population in transplant recipients. Here, using a murine model, we found that costimulatory blockade–mediated lung allograft acceptance depended on the rapid infiltration of the graft by central memory CD8⁺ T cells (CD44^hiCD62L^hiCCR7⁺). Chemokine receptor signaling and alloantigen recognition were required for trafficking of these memory T cells to lung allografts. Intravital 2-photon imaging revealed that CCR7 expression on CD8⁺ T cells was critical for formation of stable synapses with antigen-presenting cells, resulting in IFN-γ production, which induced NO and downregulated alloimmune responses. Thus, we describe a critical role for CD8⁺ central memory T cells in lung allograft acceptance and highlight the need for tailored approaches for tolerance induction in the lung.

Authors

Alexander Sasha Krupnick, Xue Lin, Wenjun Li, Ryuiji Higashikubo, Bernd H. Zinselmeyer, Hollyce Hartzler, Kelsey Toth, Jon H. Ritter, Mikhail Y. Berezin, Steven T. Wang, Mark J. Miller, Andrew E. Gelman, Daniel Kreisel